Provided herein are transgenic non-human animals whose genomes comprise two or more human genes selected from TREM1, TREML1, TREM2, TREML2, and TREML4, to methods of screening candidate agents that bind to and/or modulate the function and/or activity of at least one of the human genes in the transgenic non-human animals, and to methods of screening candidate agents to determine their effect on one or more activities and/or functions associated with expression of at least one of the human genes in the transgenic non-human animals. Further provided herein are methods of recapitulating a human TREM immune system in a non-human animal, and methods of generating a non-human animal disease model comprising a human TREM repertoire.

The present invention relates to an AAV vector carrying a predetermined hybrid HGF gene sequence. Use of the AAV vector of the present invention allows a hybrid HGF gene to be delivered to a subject at a high delivery yield.

The present invention provides viral vectors for use in the treatment and prevention of diseases associated with Schwann cells by delivering polynucleotides specifically to Schwann cells and achieving Schwann cell specific expression. The present invention has particular application in treatment and prevention of Charcot-Marie-Tooth disease and other demyelinating neuropathies. The preferred vectors are adeno-associated vectors (AAV) having a Schwann cell-specific promoter from the Myelin Protein Zero (Mpz, P0) or a minimal Mpz promoter.

Compositions including modified adeno-associated virus (AAV) vectors comprising a recombinant AAV (rAAV)-based genome are provided herein, wherein the rAAV-based genome includes one or more of: a brain derived neurotrophic factor (BDNF)-encoding cDNA insert; or a neurotrophin-3 (NT-3)-encoding cDNA insert. Also provided are methods of treating motor neuron degenerative disorders, such as amyotrophic lateral sclerosis (ALS), by administering the disclosed compositions.

Provided herein are methods of treating a subject with Cockayne Syndrome (CS) or a predisposition thereto. Also provided are methods of treating a subject with one or more mutations in an ERCC5 gene, an ERCC8 gene, an ERCC6 gene, or a combination thereof, methods of delaying the onset of Cockayne Syndrome (CS), or a symptom thereof, in a subject with one or more mutations in an ERCC5 gene, an ERCC8 gene, an ERCC6 gene, or a combination thereof, and methods of slowing, halting or reversing progression of Cockayne Syndrome (CS) in a subject. In exemplary embodiments, the method comprises administering to the subject a replication-incompetent Adeno-associated Vims (riAAV) comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein, a Cockayne Syndrome type A (CSA) protein, or a Cockayne Syndrome type B (CSB) protein in an effective amount. Provided herein are related Adeno-associated Virus and cells comprising the same.

As disclosed herein, β-arrestin1 and β-arrestin2 levels are highly elevated in brains of FTLD-tau patients suggesting that both β-arrestin1 and β-arrestin2 are elevated in the brains of patients with AD and FLTD. The current work also shows that when β-arrestin2 is overexpressed, tau levels become elevated. The data indicate that β-arrestin2 reduces tau clearance by impairing p62-mediated autophagy, a role carried out by the oligomerized form of β-arrestin2. Therefore, disclosed herein are β-arrestin oligomerization inhibitors that can be used to prevent β-arrestin oligomerization and therefore the accumulation of tau in cells, i.e. tauopathy. Also disclosed are methods of treating a tauopathy in a subject that involve administering to the subject a therapeutically effective amount of a β-arrestin oligomerization inhibitor disclosed herein.

The present disclosure provides compositions with a modulating gene expression and methods for modulating transcription.

This disclosure concerns transcription cassettes comprising nucleic acid molecules comprising a nucleotide sequence encoding AP-4 subunits; vectors comprising said transcription cassettes; pharmaceutical compositions comprising said vector; and vectors or compositions for use in the treatment of AP-4-Hereditary Spastic Paraplegia.

The present disclosure provides transgenic non-human animal (e.g., nematode) systems for assessing heterologous polygenic or monogenic phenotypes, their variants and drug discovery. The transgenic non-human animals (e.g., nematodes) contain a first heterologous polypeptide coding sequence and a second heterologous polypeptide coding sequence (a plurality of heterologous polypeptide coding sequences), wherein the first and second heterologous polypeptide coding sequences are integrated into the host animal genome, and wherein expression of the first and second heterologous polypeptide coding sequence contribute to the heterologous phenotype. The plurality of heterologous polypeptide coding sequences are interrelated wherein their expression products, directly or indirectly, contribute or lead to an observable phenotype.

The present disclosure relates to nucleic acid promoter sequences that are able to specifically express genes operatively linked to the promoter in brainstem and spinal motor neuron cells, and to methods for using such promoters to selectively express genes in motor neurons in vitro and in vivo. It is based, at least in part, on the discovery that the nucleic acid of SEQ ID NO: 1 functioned as a motor neuron-specific promoter and was successful in expressing transgenes in motor neuron cells in vivo. The present disclosure also relates to compositions that can increase the activity or expression level of miR-218 and to compositions that can decrease the expression of miR-218 target nucleic acids.